The emergence of bacterial antibiotic resistance has mobilized the search for new potent antimicrobial agents. Although much of the resistance was observed in hospital environments and related nosocomial infections, there is increasing evidence that resistant food-borne pathogens evolved due to antibiotic use in animal feed. Antimicrobial resistance phenotypes have been recognized in many zoonotic food-transmitted pathogens, including Salmonella spp., Campylobacter spp., Listeria spp., Escherichia coli O157:H7, and Yersinia spp. Consequently, there is a strong need for new antimicrobials that have suitable pharmacokinetic properties and safety profiles, with activity against these resistant pathogens. Similarly, antimicrobials of natural sources are needed for pharmaceutical, food, feed, and agricultural applications. To this end, considerable efforts have been directed at the search and isolation of new strains of bacteria and new active products of natural origin such as antimicrobial peptides (AMP).
Natural AMP are ribosomally-synthesized peptides that are produced by many species ranging from bacteria to humans. Most AMP are positively charged and contain 20 to 50 amino acid residues in length. Among AMP family is a distinct class of lanthionine (Lan)/β-methyllanthionine (MeLan)-containing peptides, termed lantibiotics.
Lantibiotics are group I bacteriocins that are synthesized and post-translationally modified by Gram-positive bacteria. These modifications generate dehydrated amino acids, i.e., α,β-didehydroalanine (Dha) and α,β-didehydrobutyric acid (Dhb) and thioether bridges of lanthionine (Lan) and β-methyllanthionine (MeLan), as well as some other less frequently encountered modifications. These modified residues are believed to stabilize molecular conformations that are essential for the antimicrobial activity of lantibiotics and their resistance to proteases of the producing strains.
Lantibiotics exhibit bactericidal activity against Gram-positive bacteria, other than the producer, generally by forming pores in cell membrane resulting in efflux of cellular components. Pores are generally formed when lantibiotics bind unspecifically to bacteria cell membrane, a wide-spread property among AMPS. However, some lantibiotics specifically target Lipid II, the precursor in cell wall synthesis, leading to pore formation. It appears more unfavorable for microbes to develop resistance to lipid II-targeting lantibiotics, compared to developing resistance to antibiotics that target a single enzyme involved in cell wall assembly. Altering a biosynthetic intermediate such as lipid II is much more challenging to targeted cells than modifying the structure of an enzyme. For example, in several cases (e.g., nisin) the lantibiotics binding site in lipid II is a motif distinctly different from the vacomycin's binding site. Due to these unique features, some lantibiotics are potent against multi-resistant and vancomycin-resistant bacterial strains.
The lantibiotics produced by lactic acid bacteria have been tested as biopreservatives in a number of food products, with nisin being the most prominent member of these bacteriocins. For decades, nisin has been used worldwide as a food additive, and it is the only lantibiotic approved by the World Health Organization as a food preservative. However, the solubility and efficacy of nisin are highly pH dependent; therefore, the bacteriocin is only useful as a preservative in acidic foods. In addition, nisin is generally inactive against Gram-negative bacteria, imposing a limitation on its usage against important food-borne pathogens, such as E. coli, Salmonella spp., Campylobacter spp., and Yersinia spp. In fact, bacteriocins with activity against Gram-negative bacteria are scarcely reported. Similarly, in spite of their antimicrobial potency, previous lantibiotics have had limited clinical applications, largely because of their poor pharmacokinetic properties.
Thus, screening for new effective lantibiotics with potentially favorable pharmacokinetic properties, as well as novel microbial strains with potent antimicrobial activity is needed.